The present invention relates to an improved synthesis for obtaining (nitroxymethyl)phenyl esters of aspirin derivatives.
These esters have interesting pharmacological and therapeutical properties; specifically they show an improved systemic and local tolerability, at the level of the gastric mucosa (WO 95/030641) and they are more effective as antithrombotic medicines (WO 97/16405).
It is known in the prior art that the (nitroxymethyl)phenyl esters of the aspirin derivatives are prepared by reacting (nitroxymethyl)phenol with the aspirin derivative in the acid form (WO 97/16405).
In particular the preparation of (nitroxymethyl)phenol is carried out starting from (hydroxymethyl)phenol through the following steps:
reaction of phenol with HBr in an organic solvent to obtain (bromomethyl)phenol;
reaction of (bromomethyl)phenol in an organic solvent with AgNO3 to form (nitroxymethyl)phenol.
The synthesis of the (nitroxymethyl)phenol intermediate has the following drawbacks. The (bromomethyl)phenol is a chemically unstable and irritant compound. The nitroxy derivative obtained from (bromomethyl-)phenol is still an unstable compound, which must be purified before reaction with the acid chloride. The (nitroxymethyl)phenol may further decompose in a not controllable way; consequently in order to obtain, on an industrial scale, the compound with the required purity for the final esterification step, the purification processes normally used in laboratory organic syntheses cannot be employed.
In conclusion the use of (nitroxymethyl)phenol in the synthesis of (nitroxymethyl)phenyl esters of aspirin derivatives is not industrially practicable.
It has been surprisingly and unexpectedly found by the Applicant that it is possible to synthetize (nitroxymethyl)phenyl esters of aspirin derivatives, and specifically (nitroxymethyl)phenyl esters of the N-acetylsalicylic acid, by synthetic reactions by which it can be avoided the use of the above mentioned phenol derivatives, and thus the purification steps of the intermediate compounds, obtaining the final products in good yields. Thus the new process is more advantageous than those of the prior art.
It is therefore an object of the present invention a new process for obtaining (nitroxymethyl)phenyl esters of aspirin derivatives of formula Rxe2x80x94COOH wherein R is selected from one of the radicals having the following formula: 
wherein:
R1 is the OCOR3 group; wherein R3 is methyl, ethyl or alkyl C3-C5, linear or branched, or the residue of a saturated heterocyclic ring having 5 or 6 atoms, containing hetero-atoms independently selected between O and N; R2 is hydrogen, halogen, C1-C4 alkyl, linear or branched when possible, C1-C4 alkoxyl, linear or branched when possible; C1-C4 perfluoroalkyl, linear or branched when possible, for example trifluoromethyl; nitro, mono- or di-(C1-4) alkylamino; R1 and R2 taken together are the dioxymethylene group, with the proviso in the formula Ib) that R1 cannot be OCOR3 in position 2 when R3 is methyl;
nI is an integer and can have the values 0 or 1;
preferably in Ia) R1 is acetoxy, preferably in ortho position with respect to the xe2x80x94COxe2x80x94 group, R2 is hydrogen;
preferably in Ib) R3=CH3, nI=0;
preferably Rxe2x80x94COOH is the acetylsalicylic acid; said process comprising the following steps, generally carried out in the presence of a solvent inert under the reaction conditions:
(1) reaction between the acid halide Rxe2x80x94C(O)xe2x80x94Xxe2x80x94 wherein:
XI is an halogen selected between Cl and Br, R is a radical as above defined, in the presence of a base, with an isomer of the hydroxybenzaldehyde, i.e., wherein the hydroxyl group can be at ortho, meta or para position, with formation of a (carbonyl)phenyl ester (I): 
(2) selective reduction of the aldehydic group of compound (I) with formation of an (hydroxymethyl)phenyl ester (II): 
(3) reaction between the (hydroxymethyl) phenyl ester of formula (II) with:
a) SOX2, X being an halogen selected between Cl and Br, with formation of an (halogenomethyl)phenyl ester of formula (III), wherein X=halogen, or
b) tosyl chloride or mesyl chloride with formation of a (tosyloxymethyl)- or (mesyloxymethyl)-phenylester, X being=O-tosyl or O-mesyl in formula (III): 
(4) reaction between the compound of formula (III) with an inorganic nitrate salt, the metal cation of which belongs to the group IB or IIB, with formation of the corresponding (nitroxymethyl) phenyl ester 
The formation of the (carbonyl)phenyl ester of step (1) can alternatively be achieved by other reactions. For example by reaction of the aspirin derivative of general formula Rxe2x80x94COOH with a dehydrating agent, such as for example N, Nxe2x80x2-dicyclohexylcarbodiimide, in the presence of an aminopyridine derivative N, N disubstituted with alkyl radicals C1-C4 (step (1I)), or with a C1-C4 alkylchloroformate in the presence of a base, soluble or insoluble in the reaction medium, as defined hereinafter (step (1II)), or with N, Nxe2x80x2 carbonyldiimidazol (step (1III)).
The process object of the present invention allows to obtain products at the required purity degree. Thus it is not necessary to purify the product compounds obtainable after each step. The overall yields are good (50-70%).
In step (1), the aspirin derivative acyl chloride or bromide, prepared from the corresponding compound in the acid form by using known reactants (ex. thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide, PCl3, PBr3), is let react in inert solvents (for example halogenated hydrocarbons such as dichloromethane, trichloromethane; ethers, such as ethyl ether, propyl ether, isopropyl ether, dioxane; esters such as ethyl acetate, propyl acetate, butyl acetate), in the presence of an organic or inorganic base, with an hydroxybenzaldehyde isomer as above defined. Said base can be soluble in the reaction solvent, as in the case of tertiary aliphatic amines of formula N(RN)3, wherein RN is an alkyl group C1-C4, such as for example tributylamine, triethylamine, diethylmethylamine, trimethylamine; or said base can either be insoluble in the solvent, such as for example in the case of alkaline inorganic salts, for example, potassium carbonate, sodium carbonate, or alkaline metal bases such as NaOH and KOH.
When step 1) is substituted with step (1I) as above defined, the aminopyridine derivative N, N disubstituted with alkyl radicals C1-C4, used in combination with the dehydrating agent, is preferably selected for example from dimethylamino pyridine and dibutylamino pyridine; when instead step (1II) is used, the compound C1-C4 alkylchloroformate is preferably selected between ethylchloroformate and isobutylchloroformate.
The reaction (2) of selective reduction of the aldehydic group to alcohol can be carried out by hydrogenation with gaseous hydrogen using conventional catalyts supported on carbon, such as for example, palladium, in a solution of the compound of formula (I) in an inert solvent. The reaction temperature is in the range 0-40xc2x0 C., the gas pressure can range from 1 to 3 atm.
In alternative to the hydrogenation with gaseous hydrogen, reduction of compound (II) can be effected also with other reducing agents, for example inorganic mixed hydrides, such as for example NaBH4, under the conditions well known to the skilled in the field.
Step (3) is carried out in an inert organic solvent at a temperature in the range 0xc2x0-40xc2x0 C.
The alternative reaction between the alcohol and the tosyl chloride or mesyl chloride is carried out according to the known methods of the prior art.
Step (4) is carried out by adding an inorganic nitrate salt which cation is selected from metals belonging to the Groups IB and IIB, to a solution of the compound of formula (III), wherein X is halogen as above defined, or O-tosyl or O-mesyl, in an organic solvent wherein said nitrate salt should be soluble, such as for example acetonitrile, tetrahydrofuran. The cation of the salt can be zinc, silver or mercury. Preferably the salt is silver nitrate. The reaction temperature can range between 20xc2x0 and 90xc2x0 C. The synthesis appears to be specific:
when in the process object of the present invention are used as starting compounds other therapeutically active molecules having a reactive carboxylic function, it is found that the corresponding nitroxymethylphenyl esters are obtained with lower yields, as it is shown in the Examples.
The following Examples are given with the only purpose to illustrate the invention and they do not limit the same.